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    Clinical Trial Results:
    Antibiotic treatment in patients with chronic low back pain and Modic Changes: a double-blind randomized placebo-controlled trial

    Summary
    EudraCT number
    		 2013-004505-14
    Trial protocol
    		 NO  
    Global end of trial date
    16 Oct 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 Jul 2021
    First version publication date
    12 Jul 2021
    Other versions
    Summary report(s)
    		 Main results
    Appendix

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    Modic02
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02323412
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Oslo University Hospital
    Sponsor organisation address
    Kirkeveien 166, Oslo, Norway, 0424
    Public contact
    Kjersti Storheim, Research and communication unit for musculoskeletal health, +47 22117751, kjersti.storheim@medisin.uio.no
    Scientific contact
    Kjersti Storheim, Research and communication unit for musculoskeletal health, +47 22117751, kjersti.storheim@medisin.uio.no
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    26 Aug 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Aug 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Oct 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To re-examine the finding that antibiotic treatment can cure patients with chronic low back pain, earlier disc herniation, and Modic changes. We will evaluate the effect of antibiotic treatment versus placebo on pain and disability, bothersomeness, health-related quality of life, sick leave, patients’ satisfaction and side effects from inclusion to 1-year follow-up. Our trial will be the first to re-examine the Danish Modic-antibiotic study.
    Protection of trial subjects
    Patients were followed up monthly during the intervention period (3 months) with blood tests (Haematological parameters (leucocytes, thrombocytes, eosinophils, haemoglobin (Hb) and hematocrit (Ht)) and measures of kidney (creatinine) and liver function (ASAT / ALAT)) together with a short clinical evaluation (blood pressure, pulse, auscultation of hearth and lunges) to monitor side effects. Adverse events (AEs) was registered at all study visits.
    Background therapy
    		 Two former clinical studies, both conducted by the same research group, have evaluated the effect of antibiotic treatment for a selected group of patients with chronic pain and MCs in the vertebrae adjacent to a previous disc herniation. The first study was an uncontrolled pilot study reporting a clinically important and statistically significant (p 0.001) improvement in all outcome measures (LBP intensity, number of days with pain, disease-specific and patient-specific function, and global perceived effect) at the end of treatment, and at long-term follow-up. The second study was a RCT concluding that the antibiotic protocol was significantly more effective for this group of patients than placebo in all the primary and secondary outcomes.
    Evidence for comparator
    		 Placebo
    Actual start date of recruitment
    01 Jun 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Norway: 180
    Worldwide total number of subjects
    180
    EEA total number of subjects
    180
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    180
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Patients were recruited from outpatient clinics at 6 hospitals in Norway from June 2015 to September 2017.

    Pre-assignment
    Screening details
    		 Patients were recruited from outpatient clinics at 6 hospitals in Norway, should be aged 18 to 65 years, low back pain for > 6 months with intensity > 5 on a 0-10 Numerical Rating Scale, lumbar disc herniation on MRI in the preceding two years, and type I and/or type II MCs.

    Pre-assignment period milestones
    Number of subjects started
    		 180
    Number of subjects completed
    		 180

    Period 1
    Period 1 title
    Baseline period
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Amoxicillin
    Arm description
    		 Amoxicillin 750 mg three times daily for 100 days
    Arm type
    		 Experimental

    Investigational medicinal product name
    Amoxicillin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    750 mg Three times daily

    Arm title
    		 Placebo
    Arm description
    		 Placebo (maiz staarch) three times daily for 100 days
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Encapsulated maize starch three times daily for 100 days

    Number of subjects in period 1
    		Amoxicillin Placebo
    Started
    89
    91
    Completed
    89
    91
    Period 2
    Period 2 title
    Treatment period, 0-3 months
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    The allocation sequence was concealed. Care providers gave each patient a prescription with a computer generated allocation number to be used at the dedicated hospital pharmacies. All care providers, research staff, statisticians, and patients were unaware of the assignment group during the data collection. Care providers, research staff and statisticians were also blinded during primary and secondary analyses and first draft of this manuscript.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Amoxicillin
    Arm description
    		 Capsulated Amoxicillin 750 mg three times daily for 100 days
    Arm type
    		 Experimental

    Investigational medicinal product name
    Amoxicillin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    750 mg Three times daily

    Arm title
    		 Placebo
    Arm description
    		 Encapsulated maize starch three times daily for 100 days
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Encapsulated maize starch three times daily for 100 days

    Number of subjects in period 2
    		Amoxicillin Placebo
    Started
    89
    91
    Completed
    86
    89
    Not completed
    3
    2
         Voluntarily discontinued study
    2
    -
         Lost to follow-up
    1
    1
         Voluntarily discontinued the study
    -
    1
    Period 3
    Period 3 title
    Follow up, 3-12 months
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Amoxicillin
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Amoxicillin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    750 mg Three times daily

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Encapsulated maize starch three times daily for 100 days

    Number of subjects in period 3
    		Amoxicillin Placebo
    Started
    86
    89
    Completed
    85
    89
    Not completed
    1
    0
         Voluntarily discontinued the study
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Amoxicillin
    Reporting group description
    		 Amoxicillin 750 mg three times daily for 100 days

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo (maiz staarch) three times daily for 100 days

    Reporting group values
    		 Amoxicillin Placebo Total
    Number of subjects
    		 89 91 180
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 44.7 ( 9.0 ) 45.2 ( 9.0 ) -
    Gender categorical
    Units: Subjects
        Female
    		 53 52 105
        Male
    		 36 39 75
    Smoking status
    Units: Subjects
        smoker
    		 25 21 46
        non-smoker
    		 64 68 132
        Not recorded
    		 0 2 2
    Educational level
    Units: Subjects
        Primary school
    		 10 9 19
        High school
    		 36 42 78
        College or university
    		 27 18 45
        University
    		 15 20 35
        Not recorded
    		 1 2 3
    Comorbidity
    Functional Comorbidity Index – Score increased by 1 for each of 18 diagnoses associated with decreased physical function.
    Units: Subjects
        Score 1 (back pain only)
    		 62 60 122
        Score 2
    		 21 27 48
        Score >2
    		 6 4 10
    Former Disc surgery
    Units: Subjects
        yes
    		 18 20 38
        no
    		 71 71 142
    Body Mass Index
    Units: kg/m2
        arithmetic mean (standard deviation)
    		 26.1 ( 4.1 ) 25.9 ( 4.0 ) -
    Subject analysis sets

    Subject analysis set title
    Intention to treat
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomized patients

    Subject analysis set title
    Per protocol
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All randomized patients without any major protocol deviation. Major protocol deviations were defined as (a) intake of < 80% of the pills (amoxicillin or placebo), (b) pause of the study medication for ≥ 2 weeks (in the antibiotic group: without other ‘relevant’ antibiotic treatment in that period), (c) ‘relevant’ antibiotic treatment in the placebo group for ≥ 4 continuous weeks between baseline and one-year follow-up, and (d) back surgery during the one-year follow-up. ‘Relevant’ antibiotic treatment was antibiotic treatment likely to affect a C. acne discitis. Further events registered as major protocol deviations were faulty inclusion (2 patients treated with antibiotics last month prior to inclusion), both amoxicillin and placebo given to patient by mistake (1 patient), and spondyloarthritis diagnosed during follow-up (1 patient).

    Subject analysis sets values
    		 Intention to treat Per protocol
    Number of subjects
    180
    155
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
    105
        Male
    75
    Smoking status
    Units: Subjects
        smoker
        non-smoker
        Not recorded
    Educational level
    Units: Subjects
        Primary school
        High school
        College or university
        University
        Not recorded
    Comorbidity
    Functional Comorbidity Index – Score increased by 1 for each of 18 diagnoses associated with decreased physical function.
    Units: Subjects
        Score 1 (back pain only)
        Score 2
        Score >2
    Former Disc surgery
    Units: Subjects
        yes
        no
    Body Mass Index
    Units: kg/m2
        arithmetic mean (standard deviation)
    ( )
    ( )

    End points

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    End points reporting groups
    Reporting group title
    Amoxicillin
    Reporting group description
    		 Amoxicillin 750 mg three times daily for 100 days

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo (maiz staarch) three times daily for 100 days
    Reporting group title
    Amoxicillin
    Reporting group description
    		 Capsulated Amoxicillin 750 mg three times daily for 100 days

    Reporting group title
    Placebo
    Reporting group description
    		 Encapsulated maize starch three times daily for 100 days
    Reporting group title
    Amoxicillin
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Subject analysis set title
    Intention to treat
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomized patients

    Subject analysis set title
    Per protocol
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All randomized patients without any major protocol deviation. Major protocol deviations were defined as (a) intake of < 80% of the pills (amoxicillin or placebo), (b) pause of the study medication for ≥ 2 weeks (in the antibiotic group: without other ‘relevant’ antibiotic treatment in that period), (c) ‘relevant’ antibiotic treatment in the placebo group for ≥ 4 continuous weeks between baseline and one-year follow-up, and (d) back surgery during the one-year follow-up. ‘Relevant’ antibiotic treatment was antibiotic treatment likely to affect a C. acne discitis. Further events registered as major protocol deviations were faulty inclusion (2 patients treated with antibiotics last month prior to inclusion), both amoxicillin and placebo given to patient by mistake (1 patient), and spondyloarthritis diagnosed during follow-up (1 patient).

    Primary: Roland-Morris Disability Questionnaire

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    End point title
    		 Roland-Morris Disability Questionnaire
    End point description
    End point type
    Primary
    End point timeframe
    1 year
    End point values
    		 Amoxicillin Placebo Amoxicillin Placebo Amoxicillin Placebo Intention to treat
    Number of subjects analysed
    88
    90
    85
    87
    85
    84
    178
    Units: 24
        arithmetic mean (standard deviation)
    12.7 ( 4.7 )
    12.8 ( 3.7 )
    10.3 ( 5.8 )
    12.4 ( 4.4 )
    9.0 ( 6.2 )
    10.7 ( 5.6 )
    12.8 ( 4.2 )
    Statistical analysis title
    		 ANCOVA on RMDQ at 1 year
    Statistical analysis description
    Compared mean RMDQ scores between the amoxicillin group and the placebo group in the whole intention-to-treat population at 1 year using ANCOVA, adjusted for baseline RMDQ score and the stratification variables; Modic type (type 1/type 2) and former disc surgery (yes/no). Missing RMDQ values were imputed with a multiple imputation model. All 180 randomized patients were included in the analysis (imputation was performed for patients with missing values).
    Comparison groups
    Amoxicillin v Placebo
    Number of subjects included in analysis
    169
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.04 [2]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.1
         upper limit
    		 0
    Variability estimate
    Standard error of the mean
    Notes
    [1] - 180 subjects analysed
    [2] - Significance level set to 0.05 (primary analysis)
    Statistical analysis title
    		 Linear Mixed Effects on RMDQ at 1 year
    Statistical analysis description
    A linear mixed-effects model for the ITT population with RMDQ as dependent variable, an interaction term between time and intervention group, treating time as a categorical variable, and with an unstructured covariance matrix.
    Comparison groups
    Placebo v Amoxicillin
    Number of subjects included in analysis
    169
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.04
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.3
         upper limit
    		 -0.1
    Variability estimate
    Standard error of the mean

    Secondary: Oswestry Disability Index

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    End point title
    		 Oswestry Disability Index
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, 3 months and 1 year
    End point values
    		 Amoxicillin Placebo Amoxicillin Placebo Amoxicillin Placebo
    Number of subjects analysed
    88
    89
    86
    85
    85
    84
    Units: 100
        arithmetic mean (standard deviation)
    31.9 ( 11.4 )
    31.8 ( 10.3 )
    26.6 ( 14.7 )
    30.4 ( 10.7 )
    24.4 ( 10.0 )
    28.9 ( 14.0 )
    Statistical analysis title
    		 ANCOVA on ODI at 1 year
    Statistical analysis description
    See ANCOVA analysis of RMDQ
    Comparison groups
    Amoxicillin v Placebo
    Number of subjects included in analysis
    169
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.007 [4]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -4.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.3
         upper limit
    		 -1.4
    Variability estimate
    Standard error of the mean
    Notes
    [3] - 179 subjects analysed
    [4] - Significance level set to 0.0167 due to multiple testing
    Statistical analysis title
    		 Linear Mixed Effects on ODI at 1 year
    Statistical analysis description
    See analysis of RMDQ
    Comparison groups
    Amoxicillin v Placebo
    Number of subjects included in analysis
    169
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.004
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -5.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.5
         upper limit
    		 -1.6
    Variability estimate
    Standard error of the mean
    Notes
    [5] - 180 subjects analysed

    Secondary: Back pain intensity

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    End point title
    		 Back pain intensity
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, 3 months an 1 year
    End point values
    		 Amoxicillin Placebo Amoxicillin Placebo Amoxicillin Placebo
    Number of subjects analysed
    88
    90
    85
    85
    85
    84
    Units: 10
        arithmetic mean (standard deviation)
    6.4 ( 1.2 )
    6.3 ( 1.5 )
    5.2 ( 2.3 )
    5.4 ( 1.9 )
    4.7 ( 2.3 )
    5.2 ( 2.3 )
    Statistical analysis title
    		 ANCOVA on Back pain intensity at 1 year
    Statistical analysis description
    See analysis on RMDQ
    Comparison groups
    Amoxicillin v Placebo
    Number of subjects included in analysis
    169
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    P-value
    		 = 0.06 [7]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.3
         upper limit
    		 0
    Variability estimate
    Standard error of the mean
    Notes
    [6] - 179 subjects included
    [7] - Significance level set to 0.0167 due to multiple testing
    Statistical analysis title
    		 Linear Mixed Effects on Back pain intensity at 1 y
    Statistical analysis description
    A LME model for the ITT population with LBP intensity as a dependent variable (with a total of 17 time points), with an interaction term between time and intervention group, treating time as a categorical variable, and an exchangeable covariance structure.
    Comparison groups
    Amoxicillin v Placebo
    Number of subjects included in analysis
    169
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [8]
    P-value
    		 = 0.005
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.2
         upper limit
    		 -0.2
    Variability estimate
    Standard error of the mean
    Notes
    [8] - 180 subjects included in analysis

    Secondary: EQ5D (Quality of life score)

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    End point title
    		 EQ5D (Quality of life score)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, 3 months and 1 year
    End point values
    		 Amoxicillin Placebo Amoxicillin Placebo Amoxicillin Placebo
    Number of subjects analysed
    89
    91
    85
    83
    84
    83
    Units: -0.59 til 1
        arithmetic mean (standard deviation)
    0.55 ( 0.19 )
    0.54 ( 0.18 )
    0.60 ( 0.22 )
    0.54 ( 0.21 )
    0.65 ( 0.22 )
    0.58 ( 0.22 )
    Statistical analysis title
    		 ANCOVA on EQ5D at 1 year
    Statistical analysis description
    See analysis on RMDQ
    Comparison groups
    Amoxicillin v Placebo
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 = 0.012 [10]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.02
         upper limit
    		 0.12
    Variability estimate
    Standard error of the mean
    Notes
    [9] - 180 subjects analysed
    [10] - Significance level set to 0.0167 due to multiple testing
    Statistical analysis title
    		 Linear Mixed Effects on EQ5D at 1 year
    Statistical analysis description
    See analysis on RMDQ
    Comparison groups
    Amoxicillin v Placebo
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.015
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.01
         upper limit
    		 0.13
    Variability estimate
    Standard error of the mean

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline to 1 year follow up
    Adverse event reporting additional description
    Trial care providers (physicians or physiotherapists) performed active surveillance of side effects/adverse events (clinical and biochemical) from baseline to 1 year. Adverse events were monitored and cross-checked against clinical patient notes, and all are reported. Same episode of AE recorded more than once is just reported as one AE here.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    4.0
    Reporting groups
    Reporting group title
    Amoxicillin
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Amoxicillin Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 89 (6.74%)
    2 / 91 (2.20%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant melanoma in situ
    Additional description: Malingnant cell contained in the resected area
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
    Additional description: Not operated
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Headache
    Additional description: Hospitalized due to headache
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Hypercholesterolaemia
    Additional description: Hospitalized due to suspicion of myocardial infarction
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
    Additional description: DVT in right groin after flight. Genetic predisposition.
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc herniation
    Additional description: Resulted in operative procedure
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 89 (2.25%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Erysipelas
    Additional description: Treated in hospital
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Amoxicillin Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    68 / 89 (76.40%)
    61 / 91 (67.03%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 89 (3.37%)
    9 / 91 (9.89%)
         occurrences all number
    5
    9
    General disorders and administration site conditions
    Flu like symptoms
    alternative assessment type: Non-systematic
         subjects affected / exposed
    8 / 89 (8.99%)
    6 / 91 (6.59%)
         occurrences all number
    10
    6
    Gastrointestinal disorders
    Diarrhoea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    20 / 89 (22.47%)
    17 / 91 (18.68%)
         occurrences all number
    24
    20
    Abdominal pain upper
         subjects affected / exposed
    7 / 89 (7.87%)
    2 / 91 (2.20%)
         occurrences all number
    7
    2
    Nausea
         subjects affected / exposed
    9 / 89 (10.11%)
    3 / 91 (3.30%)
         occurrences all number
    9
    3
    Skin and subcutaneous tissue disorders
    Rash
    alternative assessment type: Non-systematic
         subjects affected / exposed
    5 / 89 (5.62%)
    0 / 91 (0.00%)
         occurrences all number
    5
    0
    Musculoskeletal and connective tissue disorders
    Back pain
    Additional description: Not clearly defined term in this study population, as all had chronic low back pain. Meant to describe an episode of worsened low back pain that was more severe than what could be expected by the natural history.
    alternative assessment type: Non-systematic
         subjects affected / exposed
    13 / 89 (14.61%)
    18 / 91 (19.78%)
         occurrences all number
    13
    21
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    3 / 89 (3.37%)
    6 / 91 (6.59%)
         occurrences all number
    4
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/31619437
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